The present invention relates to a method for the preparation of camptothecin and camptothecin-like compounds and to novel intermediates used in this preparation.
Camptothecin and many camptothecin-like compounds, i.e., derivatives have been found to have potent cytotoxicity, and hence, are potent antitumor agents. The camptothecin moiety common to these compounds has a chiral center at the 20 position. The configuration about this position appears to be important to the antitumor activity of camptothecin and its derivatives now in clinical trials. 
Camptothecin and its derivatives can be produced using several processes taught in the art such as those described in U.S. Pat. No. 4,894,456; U.S. Pat. No. 4,399,282; U.S. Pat. No. 4,399,276; U.S. Pat. No. 4,943,579; European Patent Application 0 321 122 A2 published Jun. 21, 1989; U.S. Pat. No. 4,473,692, European Patent application No. 0 325 247 A2 published Jul. 26, 1989; European Patent application 0 556 585 A2 published Aug. 25, 1993; U.S. Pat. No. 4,981,968; U.S. Pat. No. 5,049,668; U.S. Pat. No. 5,162,532; U.S. Pat. No. 5,180,722; and European Patent application 0 540 099 A1 published May 5, 1993.
One aspect of the present invention is the preparation of the camptothecin derivative of formula (Ixe2x80x2) 
known by the chemical name xe2x80x9c7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin,xe2x80x9d which comprises cyclising the compound of formula (IIxe2x80x2) 
wherein X is halogen, particularly chloro, bromo, or iodo.
A particular aspect the invention provides a process for preparing a compound of formula (I) as shown in Scheme 1 wherein the configuration about the 20 position is (S) 
Further aspects of the present invention provide the intermediate of formula (IIxe2x80x2), particularly of formula (II), and novel intermediates used in the synthesis of the compounds of formula (IIxe2x80x2) and (II) taught herein.
Compounds of the present invention have 1 or more asymmetric carbon atoms that form enantiomeric arrangements, i.e., xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes all enantiomeric forms and any combinations of these forms. For simplicity, where no specific configuration is depicted in the structural formulas, it is to be understood that both enantiomeric forms and mixtures thereof are represented. Unless noted otherwise, the nomenclature convention, xe2x80x9c(R)xe2x80x9d and xe2x80x9c(S)xe2x80x9d denote essentially optically pure R and S enantiomers respectively. Also included in the present invention are other forms of the compounds including: solvates, hydrates, various polymorphs and the like.
Acceptable salts include, but are not limited to acid addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate; or of organic acids such as acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmoate, salicylate, oxalate, and stearate. Also within the scope of the present invention, where applicable, are salts formed from bases such as sodium or potassium hydroxide. For further examples of physiologically acceptable salts see, xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 66 (1), 1(1977).
The cyclisation process to prepare the compound of formula (Ixe2x80x2) from a compound of formula (IIxe2x80x2)via the intramolecular Heck may be carried out in the presence of a palladium catalyst such as palladium(II) acetate under basic conditions, e.g., in the presence of an alkaline earth carbonate, such as potassium carbonate in a polar, aprotic solvent, e.g., acetonitrile or dimethylformamide.
A phase transfer catalyst such as a tetraalkylammonium halide salt, e.g., tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium bromide, or tetra-n-butyl ammonium iodide, may optionally be included. A ligand for the palladium catalyst may also be included such as a triphenylphosphine, tri-o-tolyphosphine, tri-m-tolyphosphine or tri-p-tolyphosphine. In particular, the reaction may be carried out in an inert atmosphere, such as under nitrogen or argon. Suitably, the reaction mixture is heated, for example to a temperature between about 50xc2x0 to about 110xc2x0 C. for about 1 to about 24 hours. Variations on these conditions will be apparent from the literature on the Heck reaction. See, e.g., R. Grigg et al., Tetrahedron 46, 4003-4008 (1990).
Alternatively, the cyclisation process may be accomplished by a free-radical cyclisation reaction. Suitably, the reaction is carried out in a solvent such as toluene in the presence of a tin hydride, e.g., tri-n-butyltin hydride, and a radical initiator at an elevated temperature e.g. of from about 50xc2x0 C. to about 100xc2x0 C.
When the compound of formula (Ixe2x80x2) is obtained as a mixture of enantiomers, the cyclisation process may optionally be followed by a resolution step, using conventional technology known in the art, to obtain the desired enantiomer. Furthermore, when the compound of formula (Ixe2x80x2) is obtained as a free base or a salt thereof, the cyclisation process may optionally be followed by a conversion step whereby the resulting compound of formula (Ixe2x80x2) is converted into a physiologically acceptable salt or solvate thereof.
The compound of formula (II) may be prepared according to Scheme 2. 
In Step 1 of Scheme 2 a compound of formula (VIII), 1,4-benzodioxan-6-amine, commercially available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, is acylated in a Friedel-Crafts Acylation adding a halomethylketone to the 6 position producing the halo-ketone of formula (VII) (see March, Advanced Organic Chemistry, 484-487, 496-97 (1985)). The acylation can be carried out in a halogenated solvent such as dichloromethane in the presence of a Lewis acid such as boron trichloride, an acylating agent such as chloroacetonitrile, and another Lewis acid such as aluminum chloride or gallium chloride. The mixture is heated at a temperature of from about 30 to about 40xc2x0 C. To those skilled in this art, variations on these conditions will be apparent from the literature on Friedel-Crafts Acylation of anilines.
In Step 2, the halo-ketone of formula (VII) is reacted in a two-step, single vessel reaction (N-acylation followed by base-mediated Aldol condensation) producing the halomethylquinolone of formula (VI). The reaction is carried out in a polar, aprotic solvent such as acetonitrile in the presence of a suitable base such as triethylamine and an acylating agent such as an alkyl malonyl chloride, e.g., ethyl malonyl chloride, at a temperature ranging from about 0xc2x0 C. to about 30xc2x0 C., followed by the addition of more base such as sodium methoxide in methanol or triethylamine.
In Step 3, the halomethyl-quinolone of formula (VI) is converted to a haloquinoline of formula (V) using a halogenating reagent such as phosphorus oxychloride or phosphorus oxybromide. The reaction is carried out in the presence of the halogenating reagent and may use an additional cosolvent such as 1,2-dichloroethane at a temperature ranging from about 50xc2x0 C. to about 120xc2x0 C. for about 2 to about 24 hours.
In Step 4, the compound of formula (V) is transformed into the compound of formula (III) by a two-step process which may involve separate isolation of the intermediate compound of formula (IV). The compound of formula (V) is dissolved in an aprotic solvent such as dichloromethane or tetrahydrofuran and treated with N-methylpiperazine in the presence of an amine base such as triethylamine or N-methylpiperazine at a temperature of from about room temperature to about 80 OC for about 1 to 12 hours. The intermediate compound of formula (IV) may be isolated at this point. In particular, the reaction solvent may be exchanged if necessary for dichloromethane and a reducing agent such as an aluminum hydride, e.g. diisobutylaluminum hydride, is added at a temperature ranging from about room temperature (20xc2x0 C.-30xc2x0 C.) to about 37xc2x0 C. with stirring for about 1 to 12 hours.
In step 5, the compound of formula (III) is reacted with a compound of formula (IX) to give the compound of formula (II) using a Mitsunobu reaction (see O. Mitsunobu et al., Synthesis 1 (1981)). This reaction is carried out by adding a dialkylazodicarboxylate, e.g. diethylazodicarboxylate or diisopropylazodicarboxylate, to a mixture of the pyridone of formula (IX) (see Scheme 3 below) and the alcohol of formula (III), and a triaryl- or trialkylphosphine, such as triphenylphosphine or tributylphosphine in an aprotic solvent, e.g., 1,2-dimethoxyethane, tetrahydrofuran, toluene, acetonitrile, ethyl acetate, acetone, chloroform, methyl tert-butyl ether, dimethylformamide, or particularly dichloromethane, at a temperature ranging from about 0xc2x0 C. to about 40xc2x0 C. for about 1 to about 12 hours. Variation on these conditions will be apparent from the literature on the Mitsunobu reaction.
Mixtures of enantiomers of formula (IIxe2x80x2) may be prepared in an analogous manner and may be used to prepare mixtures of enantiomers of formula (Ixe2x80x2). Alternatively, if desired, the mixtures of enantiomers of formula (IIxe2x80x2) may be resolved to provide a compound of formula (II) before cyclising to provide a compound of formula (I) as shown in Scheme 1.
The compound of formula (IX) may be prepared by the process of Scheme 3: 
In Step 1 of Scheme 3, the compound of formula (XIV), 2-methoxypyridine, available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, is sequentially formylated and halogenated to yield the halopyridinecarboxaldehyde of formula (XIII). The formylation may be carried out by deprotonation at the 3-position of the pyridine ring with a base such as tert-butyllithium in a mixture of an ether solvent such as tetrahydrofuran or 1,2-dimethoxyethane, and a hydrocarbon solvent such as pentane or heptane at a temperature ranging from about xe2x88x9278xc2x0 C. to about xe2x88x9260xc2x0 C. The C-3 lithiated pyridine intermediate is then alkylated with a formylating agent such as N-formyl-N,Nxe2x80x2,Nxe2x80x2-trimethylethylenediamine at a temperature ranging from about xe2x88x9260xc2x0 C. to about xe2x88x9210xc2x0 C. The intermediate aminoalkoxy species is further deprotonated at the C-4 position using a base such as n-butyllithium. The C-4 lithiated pyridine intermediate can then be halogenated by mixing the intermediate with a solution of iodine or bromine in a polar or non-polar, organic solvent, in particular at a temperature ranging from about xe2x88x9278xc2x0 C. to about xe2x88x9245xc2x0 C. See D. Comins and M. Killpack, J Org. Chem., 55, 68-73 (1990).
In step 2, the compound of formula (XIII) is reduced then alkylated to give an ether of formula (XII). The reaction is carried out in a protic acid such as trifluoroacetic acid in the presence of an alcohol such as crotyl alcohol and a reducing agent such as a trialkylsilane, e.g., trimethylsilane or triethylsilane, at a temperature ranging from about 0xc2x0 C. to about 30xc2x0 C. Alternatively, the reaction may be carried out in an ether solvent such as tetrahydrofuran in the presence of a reducing agent such as sodium borohydride and an alcohol such as methanol at a temperature ranging from about 0xc2x0 C. to about 30xc2x0 C. followed by addition of a base such as an amide base, e.g., lithium hexamethyldisilazide, and an alkylating agent such as crotyl bromide at a temperature ranging from about 0xc2x0 C. to about 30xc2x0 C.
The transformation of step 3 may be carried out in two stages, i.e., steps 3a and 3b. In step 3a the compound of formula (XII) may be cyclized by an intramolecular Heck reaction to form the compound of formula (XI). The reaction may be carried out in the presence of a palladium catalyst, e.g., palladium acetate, under basic conditions in a polar, aprotic solvent, e.g., acetonitrile or dimethyl-formamide) or a polar, protic solvent, e.g., n-propanol, i-propanol, or t-butanol. A phase transfer catalyst such as a tetraalkylammonium halide salt, e.g., tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide may be included especially when a polar, aprotic solvent is used. A ligand for the palladium catalyst may also be included such as a triphenylphosphine, tri-o-tolylphosphine, tri-m-tolylphosphine, or tri-p-tolylphosphine. An isomerization catalyst, e.g., tris(triphenylphosphine)rhodium(l) chloride, may also be included. The reaction should be carried out in an inert atmosphere, such as under nitrogen or argon gas at a temperature ranging from about 50xc2x0 C. to about 110xc2x0 C. for about 1 to about 24 hours. The intermediate of formula (XIa) may be isolated but this is not necessary. Variations on these conditions will be apparent from the literature on the Heck reaction. See, e.g., R. Grigg et al. Tetrahedron 46, 4003-4008 (1990).
In step 3b, the compound of formula (XI) may be transformed to the compound of formula (X) by i) dihydroxylation using a catalytic asymmetric dihydroxylation and ii) oxidation of the resultant diol. The dihydroxylation reaction is carried out in the presence of an osmium catalyst, e.g., potassium osmate (VI) dihydrate, osmic chloride hydrate or osmium tetroxide, a chiral tertiary amine catalyst, e.g., derivatives of the cinchona alkaloids such as 2,5-diphenyl-4,6-bis(9-O-dihydroquinidyl)pyrimidine, a stoichiometric oxidizing reagent, e.g., potassium ferricyanide, hydrogen peroxide or N-methylmorpholine N-oxide, and a primary amide, e.g., methanesulfonamide, under basic conditions, e.g., in the presence of potassium carbonate, in an aqueous mixture containing a polar protic solvent, e.g., t-butanol, i-propanol, n-propanol. The reaction can be carried out at a temperature ranging from about 0 to about 25 xc2x0 C. for about 48 hours. See K. B. Sharpless, et al., J. Org. Chem. 58, 3785-3786 (1993). The oxidation of the intermediate diol can be carried out in the presence of an oxidizing reagent, e.g., iodine, in a polar, protic medium, e.g., aqueous methanol, aqueous tertbutanol or aqueous n-propanol, in the presence of a base, e.g., calcium carbonate, at a temperature ranging from about 0xc2x0 C. to about 25xc2x0 C.
In step 4, the methoxypyridine of formula (X) may be converted to the pyridone of formula (IX) in a polar, protic solvent, e.g., water, in the presence of a protic acid, e.g., hydrochloric acid, at a temperature ranging from about 25xc2x0 C. to about 100xc2x0 C. for about 1 to about 6 hours. Alternatively, the conversion of (X) to (IX) may be carried out in a polar, aprotic solvent such as acetonitrile in the presence of a trialkylsilylhalide, e.g., trimethylsilyliodide, at a temperature ranging from about 25xc2x0 C. to about 85xc2x0 C. for about 1 to about 24 hours.